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Realization of tristability in a multiplicatively coupled dual-loop genetic network.

ABSTRACT: Multistability is a crucial recurring theme in cell signaling. Multistability is attributed to the presence of positive feedback loops, but the general condition and essential mechanism for realizing multistability remain unclear. Here, we build a generic circuit model comprising two transcription factors and a microRNA, representing a kind of core architecture in gene regulatory networks. The circuit can be decomposed into two positive feedback loops (PFLs) or one PFL and one negative feedback loop (NFL), which are multiplicatively coupled. Bifurcation analyses of the model reveal that the circuit can achieve tristability through four kinds of bifurcation scenarios when parameter values are varied in a wide range. We formulate the general requirement for tristability in terms of logarithmic gain of the circuit. The parameter ranges for tristability and possible transition routes among steady states are determined by the combination of gain features of individual feedback loops. Coupling two PFLs with bistability or one NFL with a bistable PFL is most likely to generate tristability, but the underlying mechanisms are largely different. We also interpret published results and make testable predictions. This work sheds new light on interlinking feedback loops to realize tristability. The proposed theoretical framework can be of wide applicability.

SUBMITTER: Huang B

PROVIDER: S-EPMC4932522 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Realization of tristability in a multiplicatively coupled dual-loop genetic network.

Huang Bo B Xia Yun Y Liu Feng F Wang Wei W

Scientific reports 20160705

Multistability is a crucial recurring theme in cell signaling. Multistability is attributed to the presence of positive feedback loops, but the general condition and essential mechanism for realizing multistability remain unclear. Here, we build a generic circuit model comprising two transcription factors and a microRNA, representing a kind of core architecture in gene regulatory networks. The circuit can be decomposed into two positive feedback loops (PFLs) or one PFL and one negative feedback ...[more]

PMID: 27378101

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Project description:Data from C57BL/6J (B6) × DBA/2J (D2) F2 intercrosses (B6xD2 F2 ), standard and recombinant inbred strains, and heterogeneous stock mice indicate that a reciprocal (or inverse) genetic relationship exists between alcohol consumption and withdrawal severity. Furthermore, some genetic studies have detected reciprocal quantitative trait loci (QTLs) for these traits. We used a novel mouse model developed by simultaneous selection for both high alcohol consumption/low withdrawal and low alcohol consumption/high withdrawal and analyzed the gene expression and genome-wide genotypic differences.Randomly chosen third selected generation (S3 ) mice (N = 24/sex/line), bred from a B6xD2 F2 , were genotyped using the Mouse Universal Genotyping Array, which provided 2,760 informative markers. QTL analysis used a marker-by-marker strategy with the threshold for a significant log of the odds (LOD) set at 10. Gene expression in the ventral striatum was measured using the Illumina Mouse 8.2 array. Differential gene expression and the weighted gene co-expression network analysis (WGCNA) were implemented.Significant QTLs for consumption/withdrawal were detected on chromosomes (Chr) 2, 4, 9, and 12. A suggestive QTL mapped to Chr 6. Some of the QTLs overlapped with known QTLs mapped for 1 of the traits individually. One thousand seven hundred and forty-five transcripts were detected as being differentially expressed between the lines; there was some overlap with known withdrawal genes (e.g., Mpdz) located within QTL regions. WGCNA revealed several modules of co-expressed genes showing significant effects in both differential expression and intramodular connectivity; a module richly annotated with kinase-related annotations was most affected.Marked effects of selection on expression and network structure were detected. QTLs overlapping with differentially expressed genes on Chr 2 (distal) and 4 suggest that these are cis-eQTLs (Chr 2: Kif3b, Kcnq2; Chr 4: Mpdz, Snapc3). Other QTLs identified were on Chr 2 (proximal), 9, and 12. Network results point to involvement of kinase-related mechanisms and outline the need for further efforts such as interrogation of noncoding RNAs.

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Realization of tristability in a multiplicatively coupled dual-loop genetic network.

Publications

Realization of tristability in a multiplicatively coupled dual-loop genetic network.

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